Although many studies have demonstrated linkage between genetic markers and quantitative trait loci (QTL) in commercial animal populations, the actual DNA polymorphisms responsible for the observed effects—a quantitative trait nucleotide (QTN), has been identified in only a single case in dairy cattle (a polymorphism in exon 8 of the gene encoding acylCoA:diacyglycerol acyltransferase DGAT1) on Bos taurus chromosome 14 (BTA 14), which was associated with increased fat yield, fat and protein percent, as well as decreased milk and protein production. This gene was identified using bioinformatics, comparative mapping, and functional analysis.
Various studies have proposed candidate genes for the QTL on BTA6 based on their putative physiological role on the trait of interest. PPARGC1A (peroxisome proliferator activated receptor gamma, coactivator 1, alpha) was suggested as a positional and functional candidate gene for the QTL on BTA6, due to its key role in energy, fat, and glucose metabolism. The function of PKD2 corresponds with the QTL effect. This gene encodes an integral membrane protein involved in intracellular calcium homoeostasis and other signal transduction pathways. SPP1 was set forth as having an essential role in mammary gland differentiation and branching of the mammary epithelial ductal system, and is therefore a prime candidate. Furthermore, anti-sense SPP1 transgenic mice displayed abnormal mammary gland differentiation and milk secretion.
Segregating quantitive trait loci (QTL) for milk production traits on chromosome BTA6 were reported in U.S. Holsteins, British black and white cattle, Norwegian cattle, and Finnish Ayrshires. Three QTLs affecting milk, fat, and protein production, as well as fat and protein concentration are segregating on BTA6 in the Israeli Holstein population. The QTL with the greatest significance was located near the middle of the chromosome, with a confidence interval of 4 cM for protein percentage centered on microsatellite BM143. Two unrelated Israeli sires were found to be heterozygous for this QTL, whereas seven other sires were homozygous for the QTL.
The QTL confidence interval on BTA6 is orthologous to two regions on both arms of human chromosome 4 (HSA4) that contain the following annotated genes: FAM13A1, HERC3, HERC5, HERC6, PPM1K, ABCG2, PKD2, SPP1, MEPE, IBSP, LAP3, MED28, KIAA1276, HCAP-G, MLR1, and SLIT2. Physical mapping and combined linkage and linkage disequilibrium mapping determined that this QTL is located within a 420 Kbp region between genes ABCG2 and LAP3.
ABCG2, a member of the ATP binding cassette (ABC) superfamily, is a ‘halftransporter,” with only one ATP binding cassette in the N-terminus and one C-terminal transmembrane domain. In an ATP dependent process, ABCG2 transports various xenobiotics and cytostatic drugs across the plasma membrane. Analysis of different stages of mammary development by immunohistochemistry and western analysis revealed that ABCG2 was not expressed in virgin mice, but was greatly induced during late pregnancy and especially during lactation. ABCG2 expression is confined to the apical membrane of alveolar; but not ductal mammary epithelial cells of mice, cows, and humans; and is responsible for the active secretion of clinically and toxicologically important substrates into mouse milk. Mice homozygous for an ABCG2 knock-out mutation lack this function. However, −/−mice and their suckling progeny showed no adverse effects. ABCG2 is thought to be a drug transporter, but it is induced by estrogen. Related genes i.e. ABCG1, 5, and 8 are sterol transporters. It is therefore reasonable to propose that ABCG2 might transport cholesterol into milk.
Whereas in other tissues ABCG2 generally has a xenotoxin-protective function, transfer of xenotoxins from the mother to the suckling infant or young via milk is difficult to reconcile with a protective role.
As compared to other agricultural species, dairy cattle are unique in the value of each animal, the long generation interval, and the very limited fertility of females. Thus unlike plant and poultry breeding, most dairy cattle breeding programs are based on selection within the commercial population. Similarly, detection of quantitative trait loci (QTL) and marker assisted selection (MAS) programs are generally based on analysis of existing populations. The specific requirements of dairy cattle breeding has led to the generation of very large data banks in most developed countries, which are available for analysis.